Very few drugs are known which are effective mild analgesics. Aspirin and related salicylates are known to relieve mild to moderate pain. However, the salicylates are known to possess a number of very undesirable side effects such as nausea, vomiting, epigastric distress, gastric ulceration and even hemorrhaging. Arthritis patients who are on high doses of salicylate analgesics have reported peptic ulcer symptoms and gastritis. Aspirin is also one of the leading accidental poisoners of children.
Acetaminophen is sold widely for treating mild pain. Acetaminophen is useful in patients who for whatever reason cannot tolerate salicylates. However, some are sensitive to acetaminophen and it is apparently exhibits hepatotoxicity.
The primary drugs available for alleviating severe pain such as pain from fractures, surgery, cancer, back, kidney stones, etc. were the narcotics including both the naturally occurring and synthetic ones. These include morphine, meperidine, codeine, methadone, levorphanol, oxycodone, hydromorphone, and alphaprodine. These narcotic analgesics have the distinct and severe disadvantage of causing physical dependence (addiction), sedation, constipation, nausea, etc.
The more important anti-anxiety agents on the market are benzodiazepines primarily diazepam, chlordiazepoxide, oxazepam and clorazepate. While these agents are of value they can produce drowsiness, fatigue, ataxia and other side effects. The anti-psychotic agents such as chlorpromazine are useful but have undesirable side effects especially drowsiness, jaundice and agranulocytosis.
Hence, there is a definite need to have both better mild, moderate and strong analgesic agents as well as better psychotherapeutic agents. The present invention helps fill these needs.
In 1975 J. Hughes et al. reported in Nature 258, 577 (1975) the opiate-like analgesic activity of 2 pentapeptides: ##STR2##
Since that time a number of enkephalin-like pentapeptides have been synthesized which are more stable and have high analgesic activity. Generally, these pentapeptides are ones in which the second amino acid (glycine) and/or the fifth amino acid (methionine or leucine) have been modified. Modification of the first, third or fourth amino acid generally leads to an inactive peptide. See, R. C. A. Frederickson, Life Sciences 21, 23 (1977); C. R. Beddell et al., Proc. R. Soc. Lond 198, 249 (1977); A. S. Cutta et al., Life Sciences 21, 559 (1977); D. Roemer et al., Nature 268, 547 (1977) and B. vonBraffenried et al., Nature 272, 729 (1978).
Various substituted piperazinones are known, see R. M. Genck-Sas-Berekowsky and I. H. Spinner, Can. J. Chem. 48, 163 (1970); D. B. Haydock and T. P. C. Mulholland, J. Chem. Soc. (C) 2390 (1971); M. Mashehan et al., Bull. Chem. Soc. Jap. 46, 844 (1978) and H. Vihida and M. Ohta, ibid 46, 3612 (1973). However, none of those compounds are known to possess analgesic or psychotherapeutic activity.